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Elife. 2013 May 28;2:e00498. doi: 10.7554/eLife.00498.

Pharmacological brake-release of mRNA translation enhances cognitive memory.

Author information

1
Department of Biochemistry and Biophysics , University of California, San Francisco , San Francisco , United States ; Howard Hughes Medical Institute, University of California, San Francisco , San Francisco , United States.

Abstract

Phosphorylation of the α-subunit of initiation factor 2 (eIF2) controls protein synthesis by a conserved mechanism. In metazoa, distinct stress conditions activate different eIF2α kinases (PERK, PKR, GCN2, and HRI) that converge on phosphorylating a unique serine in eIF2α. This collection of signaling pathways is termed the 'integrated stress response' (ISR). eIF2α phosphorylation diminishes protein synthesis, while allowing preferential translation of some mRNAs. Starting with a cell-based screen for inhibitors of PERK signaling, we identified a small molecule, named ISRIB, that potently (IC50 = 5 nM) reverses the effects of eIF2α phosphorylation. ISRIB reduces the viability of cells subjected to PERK-activation by chronic endoplasmic reticulum stress. eIF2α phosphorylation is implicated in memory consolidation. Remarkably, ISRIB-treated mice display significant enhancement in spatial and fear-associated learning. Thus, memory consolidation is inherently limited by the ISR, and ISRIB releases this brake. As such, ISRIB promises to contribute to our understanding and treatment of cognitive disorders. DOI:http://dx.doi.org/10.7554/eLife.00498.001.

KEYWORDS:

ATF4; Human; Mouse; Rat; eIF2; eIF2B; integrated stress response; memory consolidation; unfolded protein response

PMID:
23741617
PMCID:
PMC3667625
DOI:
10.7554/eLife.00498
[Indexed for MEDLINE]
Free PMC Article
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